D1-like dopamine receptors in the dentate gyrus mediate cannabidiol's facilitation of extinction and prevention of reinstatement in methamphetamine-induced conditioned place preference.

Methamphetamine (METH) is a highly addictive psychostimulant, and despite its widespread abuse, there are no FDA-approved treatments for METH use disorder (MUD). Cannabidiol (CBD), a non-psychoactive cannabinoid, has shown promise in reducing behaviors linked to psychostimulant use, including METH. However, the underlying neurobiological mechanisms remain unclear. Emerging evidence suggests that CBD may act on the dopamine system to influence drug-seeking behavior. D1-like dopamine receptors (D1Rs) in the hippocampus (HPC) are involved in memory processes related to rewards, which may contribute to CBD's effects. This study examined whether D1Rs in the dentate gyrus (DG) region of the HPC play a role in CBD's modulation of METH-induced conditioned place preference (CPP) during extinction and reinstatement. Adult male Wistar rats received the D1Rs antagonist SCH23390 (0.25, 1, and 4 μg/0.5 μl saline) into the DG region before intracerebroventricular injection of CBD (10 and 50 μg/5 μl of 12 % DMSO). Results show that the highest dose of SCH23390 (4 μg) significantly blocked CBD's ability to enhance extinction of METH-CPP. Moreover, SCH23390 (1 and 4 μg) reversed CBD's prevention of reinstatement of METH-CPP. These findings suggest that D1Rs in the DG region are involved in mediating CBD's effects and offer insights into its therapeutic potential for MUD.